Glutamate, the main excitatory neurotransmitter in the central nervous system, is necessary for many normal neurological functions, including learning and memory. Overactivation of glutamate receptors, however, and resulting excitotoxic neuronal injury, has been implicated in the pathogenesis of neuronal loss in the central nervous system (CNS) following several acute insults, including hypoxia/ischemia (Simon et al., 1984; Meldrum, 1985; Rothman and Olney, 1986; Sheardown et al., 1990), trauma (Faden and Simon, 1988), epilepsy (Griffiths et al., 1984), and certain neurodegenerative disorders (Greenamayre et al., 1985; Choi, 1988; Meldrum and Garthwaite, 1990; Olanow, 1990; Beal, 1992).
Oxidative stress, caused by reactive oxygen species, represents another injury mechanism implicated in many of the same acute and chronic diseases (Flamm et al., 1978; Chan et al, 1985; Kontos and Wei, 1986; Siesjo et al., 1989; Braughler and Hall, 1989; review Halliwell, 1992). Reactive oxygen species (e.g., superoxide radical) would cause oxidative damage to cellular components, such as peroxidation of cell membrane lipids, inactivation of transport proteins, and inhibition of energy production by mitochondria (Halliwell, 1992).
These two events, glutamate excitotoxicity and oxidative stress, may be interlinked; reactive oxygen species formation may occur as a direct consequence of glutamate receptor overstimulation (Dugan et al., 1992; Lafon-Cazal et al., 1993) and thus mediate a component of glutamate neurotoxicity (Choi, 1988; Coyle and Puttfarcken, 1993). Excitotoxicity, in turn, can be reduced by free radical scavengers, including C, Zn-superoxide dismutase and catalase (Dykens et al., 1987; Chan et al., 1990), the 21-aminosteroid "lazaroids" (Monyer et al., 1990), the vitamin E analog, trolox (Chow et al, 1994), spin-trapping agents such as phenylbutyl-N-nitrone (Yue et al., 1992), and the ubiquinone analog, idebenone (Bruno et al., 1994) which reduce the amount of reactive oxygen species.
Free radical scavengers are neuroprotective in in vitro as well as in vivo models of traumatic or hypoxic/ischemic CNS injury. N-methyl-D-aspartate and AMPA/kainate receptor antagonists are neuroprotective in oxygen-glucose deprivation injury in vitro (Choi, 1988; Goldberg and Choi, 1993), and reduce loss of brain tissue in animal models of ischemia (Simon et al., 1984; Sheardown et al., 1990). Free radical scavengers also protect against excitotoxic neuronal death in vitro (Dykens et al., 1987; Monyer et al., 1990), and reduce ischemic injury in vivo (Liu et al., 1989; Imaizumi et al., 1990; Lesiuk et al., 1991; Rosenthal et al., 1992). Transgenic animals which overexpress the free radical scavenger enzyme, CuZn superoxide dismutase (SOD), are resistant to glutamate toxicity (Chan et al., 1990), and ischemic brain injury (Chan et al., 1991; Kinouchi et al., 1991).
Programmed cell death, or apoptosis, also contributes to cell death in certain neurologic disease states. For example, apoptosis would mediate delayed neuronal degeneration days after ischemia-reperfusion (Dessi et al., 1994; McManus et al., 1994), and would be a factor in neuronal cell death in certain neurodegenerative diseases (Mochizuki et al., 1994). Oxidative stress due to free radical oxygen species would be one of the insults that can trigger apoptosis (Raff, 1992; Verity, 1994; Stewart, 1994), so that free radical scavengers would also be able to limit programmed cell death (Ratan et al., 1994; Franklin et al., 1994). Bcl-2 appears to act on a free radical scavenging pathway to mediate its cytoprotective effects against apoptosis (Hockenbery et al., 1993).